During the last few years, chronic kidney disease (CKD) has been increasingly recognized as a significant risk factor for the development of cardiovascular disease. An American Heart Association Scientific Statement reviewing this subject was published last fall.1 This paper pointed out that NCEP-ATPIII did not include renal abnormalities as part of the risk factor spectrum impacting cholesterol management guidelines, although the National Kidney Foundation has previously published practice guidelines regarding dyslipidemia in CKD patients. Two recent reports in the New England Journalof Medicine further confirm a link between renal abnormalities and the subsequent development of significant cardiovascular
disease (CVD), as well as increased morbidity and mortality. The
degree of awareness of these issues in the cardiology community is
unclear; it is imperative that physicians recognize that evidence of
CKD, based on glomerular filtration rate (GFR), creatinine, or albuminuria, are now recognized to be of clinical significance.

A large registry from Kaiser Permanente of Northern California reports a significant "independent graded association" between decreased GFR and the risk of CVD morbidity as well as death.2 This study utilized longitudinal measures of estimated GFR, using the Modification of Diet in Renal Disease (MDRD) GFR equation. All adults over 20 were entered into a Kaiser Permanente Renal Registry; those with significant renal disease were excluded. The initial measurement of GFR was established as baseline; changes during follow-up were estimated from serum creatinine determinations. GFR was normalized to body surface area (1.73 m). Serum albumin and proteinuria were measured, and socioeconomic status was assessed. The primary end point was total mortality, CV events, and hospitalizations from January 1996 to December 2000. Event rates were adjusted for age and the independent effect of GFR. Multiple variables that affect GFR outcomes were entered into the final model, including age, cardiovascular
events, and hospitalization. The cohort included 1.12 million adults; the
median number of serum creatinine measurements were 3. Estimated
GFR was assessed in all using the MDRD equation.

Results: Individuals who had a decrease in GFR had a higher prevalence of CV disease, proteinura, diabetes, and hypertension, and were older than those with a normal GFR. The median follow-up was 2.8 years, amounting to 3.132 million person
years. The main finding was that age-standardized rates of death, CV events, and
hospitalizations increased substantially with progressively lower GFR. A baseline
GFR of = 60 mL per minute per 1.73 m2 was the reference. After adjustment for multiple factors, including social demographic characteristics and the presence of prior CV disease, it was found that "the risk of death increased sharply as estimated GFR declined" risk increased 17% in the GFR 45-59 group; an increase 343% was found with an initial GFR of < 15. Repeat hospitalizations increased proportionally to the decrease
in the GFR. Proteinuria was an independent predictor for
death, cardiovascular events, and hospitalization. A
greater risk of an adverse event increased markedly once GFR fell below 45mL per minute per 1.73 m2.

Sarnak and colleagues cite other surveys that have linked increased CVD risk with higher creatinine levels including NHANES II, where a GFR < 70 was associated with a 68% increased risk of death from any cause, and a 50% increase risk of death from CV, compared to a
GFR > 90. In the Kaiser cohort, the relationship between
GFR and major end points was not linear, with risk rising substantially at a GFR < 60, and an even sharper
decline when baseline GFR was < 45.

Discussing the potential causes for the relationship between CKD and mortality and cardiovascular disease, Sarnak et al point out that low GFR individuals had a greater prevalence of pre-existing CV disease, CV risk factors, and co-existing morbid conditions. The published literature suggests increased inflammatory markers, abnormal lipoprotein levels, elevated homocysteine levels, increased coagulability, anemia, endothelial dysfunction, and increased vascular calcification. Sarnak et
al suggest that their results are more generalizable than
most other reports due to the very large and ethnically
diverse population. Furthermore, they emphasize the
usefulness of serial estimates of GFR as morbid, and mortal events are markedly increased GFR < 45.

Another publication comes from the VALIANT Trial, a randomized study assessing the usefulness of an ACE inhibitor vs anangiotensin receptor blocker post acute myocardial infarction.3 In this study, 14500 patients with acute MI and heart failure were randomized to captopril, valsartan, or both. GFR was measured by the MDRD equation, and a large number of variables were assessed. Subjects were randomized up to 12 days post MI, and had to have LV systolic dysfunction, clinical, or X-ray evidence of heart failure. Mean follow-up was 24.7 months. Baseline creatinine had to be < 2.5 mg/dL. Results: The primary end point was death from any cause. Multiple secondary end points were assessed. The patients were grouped into GFR strata of > 75% mL/minute/1.73 m2;
60-74, 45-59, and less than 45. Mortality rose incrementally
with each decrement of GFR. Baseline estimated GFR
demonstrated a normal distribution, (mean GFR of 70). Thirty-eight percent of 14500 patients had a GFR = 75 at baseline, whereas 28% had an estimated GFR of 45-60, and 11% had a GFR of < 45. CKD criteria were present in 34%, even though creatinine was 2.5 or less at entry. Unadjusted 3-year mortality was 14% in the highest GFR cohort, 20.5% in those with a GFR 60-75, and 45.5% in the individuals with GFR < 45. Event curves diverged early. The composite end point tracked with mortality; all groups with a lower GFR (< 75) had worse outcomes, with a hazard ratio of 1.5 for the lowest GFR cohort. Treatment assignment of study drug had no effect on outcomes. Pre-existing renal disease was common, and as with the Kaiser study, Sarnak et al strongly recommend the routine use of the MDMR equation to calculate GFR.

Anavekar and colleagues point out that the Framingham
risk scoring system underestimates cardiovascular risk in
CKD patients. Risk factor modification and interventional
therapies were lower than the general population.

Anavekar et al conclude that in post MI patients, "preexisting renal impairment should be considered a potent,
independent, and easily identifiable risk factor for cardiovascular complications."

Comment by Jonathan Abrams,
MD

An excellent editorial by Hostetter, in the same issue of the New England Journal of Medicine, discusses the issue of whether CKD is a marker or a player, or perhaps both, with respect to CV complications, including death.4 He points out that CKD individuals "have an excess of traditional risk factors for cardiovascular disease," but that "predisposition. . . persists even after adjustment for the overabundance of standard risk factors." Multiple metabolic and prothrombotic risk are found in CKD. These individuals may be detected by measurements of urinary protein, creatinine, or by the estimated GFR technique. Renal experts have repeatedly pointed out that serum creatinine is an imprecise measure of renal function, depending in part on body mass (eg, young healthy males vs elderly frail females), thus serum creatinine does not adequately indicate whether GFR is depressed. It would appear that no matter how CKD is diagnosed (eg, the estimated GFR formula, serum creatinine, micro or macro albuminura), the diagnosis establishes high risk either because of existing CKD, or because of the multiple non-renal factors that are likely to be deranged in such individuals. The data from the VALIANT Trial suggests that traditional risk factors in this CKD population cannot explain all of the increased risk, and this is echoed by other reports. Thus, for the prevention oriented physician and cardiologist who treat patients with evidence of CKD, the new paradigm is to aggressively treat all identifiable risk factors, and perhaps to lower LDL cholesterol to 100 mg/dL or lower. There is no trial data available to support this recommendation, but
it seems reasonable. CKD now joins the list of major coronary risk factors, such as hypertension, smoking, dyslipidia, and diabetes. CKD individuals are often undertreated for these same risk factors, and may be deprived of
revascularization strategies due to the concerns of renal
embarrassment from contrast during coronary angiography and other complications. The adverse outcomes documented in these reports suggest that a hands off approach
to these individuals must be abandoned.

Dr. Abrams, Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque, is on the Editorial Board of Clinical Cardiology Alert.